Plausible estimates of the annual US mortality linked to domestic radon exposure vary from 0 to 40,000. This wide range is largely a result of uncertainties in the various assumptions and extrapolations necessary to produce an epidemiologically-based risk estimate. This project brings together and links three projects in experimental radiation biology, within a strong theoretical framework provided by a modelling project; it is specifically targeted ar reducing uncertainties in extrapolation, particularly from high to low dose, from high to low dose rate, and between different radiation qualities. Based on a detailed analysis of the sources of uncertainty in estimating domestic radon risk, our five goals are 1) Understanding how to extrapolate radon risks down to very low doses, corresponding to an average of less than one a particle per cell; 2) Assessment of appropriate quality factors for radon; 3) Evaluation of the significance of a-particle exposure time; 4) Investigation of the interaction between a-particles and other lung carcinogens; 5) Investigation of characteristic biomarkers of a-particle exposure. Because of the stochastic nature of the endpoint of interest in humans (lung cancer), our three in vitro experimental projects focus on mutation, chromosomal aberration and oncogenic transformation. In each case our overall aims are guided by the needs of domestic radon risk estimation, and the modelling project is designed to analyze the experimental results and apply the conclusions to risk estimation. A key component of this proposal is the single-particle microbeam, which makes it possible to deliver exact numbers of a-particles to individual cells, including a single particle. In the last year, the speed at which we can deliver known numbers of a particles to single cells has increased by an order of magnitude. The central issue is to assess cancer risks in the domestic situation where cells of the bronchial epithelium are essentially never traversed by more than one a-particle in a life-time, by extrapolation from underground miner data where multiple traversals are common. The focus of this proposal is to use the microbeam with all of the biological systems listed above, further complicating factors being dose prolongation and the presence of other carcinogens.